1. Field of the Invention
The invention relates to pyridone-containing peptidomimetic compounds that advantageously inhibit the enzymatic activity of picornaviral 3C proteases, especially rhinovirus 3C proteases (RVPs), and that retard viral growth in cell culture. The invention also relates to the use of these compounds in pharmaceutical compositions, methods of treatment of rhinoviral infections using these compounds and compositions, and processes for the synthesis of these compounds and compounds useful in the syntheses thereof.
2. Related Background Art
The picomaviruses are a family of tiny non-enveloped positive-stranded RNA-containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis virus, foot and mouth viruses, hepatitis A virus, and others. The human rhinoviruses are a major cause of the common cold. To date, there are no effective therapies on the market that cure the common cold, only treatments that relieve the symptoms.
Picornaviral infections may be treated by inhibiting the proteolytic picornaviral 3C enzymes. These enzymes are required for the natural maturation of the picornaviruses. They are responsible for the autocatalytic cleavage of the genomic, large polyprotein into the essential viral proteins. Members of the 3C protease family are cysteine proteases, where the sulfhydryl group most often cleaves the glutamine-glycine amide bond. Inhibition of 3C proteases is believed to block proteolytic cleavage of the viral polyprotein, which in turn can retard the maturation and replication of the viruses by interfering with viral particle production. Therefore, inhibiting the processing of this cysteine protease with selective small molecules that are specifically recognized should represent an important and useful approach to treat and cure viral infections of this nature and, in particular, the common cold.
Some small-molecule inhibitors of the enzymatic activity of picornaviral 3C proteases (i.e., antipicornaviral compounds) have been recently discovered. See, for example: U.S. Pat. No. 5,856,530; U.S Pat. No. 5,962,487; U.S. patent application Ser. No. 08/991,282, filed Dec. 16, 1997, by Dragovich et al.; and U.S. patent application Ser. No. 09/301,977, filed Apr. 29, 1999, by Dragovich et al. See also: Dragovich et al., xe2x80x9cStructure-Based Design, Synthesis, and Biological Evaluation of Ireversible Human Rhinovirus 3C Protease Inhibitors . . . ,xe2x80x9d J. Med. Chem. (1999), Vol. 42, No. 7, 1203-1212, 1213-1224; and Dragovich et al., xe2x80x9cSolid-phase Synthesis of Irreversible Human Rhinovirus 3C Protease Inhibitors . . . ,xe2x80x9d Bioorg. and Med. Chem. (1999), Vol. 7, 589-598. There is still a desire, however, to discover small-molecule compounds that are especially potent antipicornaviral agents.
Inhibitors of other related cysteine proteases such as cathepsins have been described in, e.g., U.S. Pat. No. 5,374,623; U.S. Pat. No. 5,498,616; and WIPO International Publication Nos. WO 94/04172, WO 95/15749, WO 97/19231, and WO 97/49668. There yet remains a need for inhibitors targeting the picornaviral 3C cysteine protease with desirable pharmaceutical properties, such as high specificity.
This invention relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the general formula: 
wherein:
Ra is substituted or unsubstituted heterocycloalkyl or heterocycloalkylalkyl;
Rb is a substituent having the formula: 
wherein:
Rf and Rg are independently H or lower alkyl;
m is 0 or 1;
p is an integer of from 0 to 5;
A1 is CH or N;
A2 is C(Rh)(Ri), N(Rj), S, S(O), S(O)2, or O; where each Rh, Ri, and Rj is independently H or lower alkyl;
each A3 present is independently C(Rh)(Ri), N(Rj), S, S(O), S(O)2, or O; where each Rh, Ri, and Rj is independently H or lower alkyl;
when p is 1, 2, 3, 4, or 5, A4 is N(Rk), C(Rh)(Ri), or O; and when p is 0 (i.e., A3 is not present), A4 is N(Rk)(Rl), C(Rh)(Ri)(Rj), and O(Rl), where each Rh, Ri, and Rj is independently H or lower alkyl, each Rk is H, alkyl, aryl, or acyl, and each R1 is H, alkyl, or aryl;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present (i.e., m=1) and a hydrogen atom when A2 is absent (i.e., m=0);
Rc is H, halogen or a substituted or unsubstituted lower alkyl group;
Rd is H, halogen, hydroxyl, a substituted or unsubstituted alkyl, alkoxy or alkylthio group;
Re is H or a substituted or unsubstituted alkylgroup; and
Z and Z1 are independently H, F, a unsubstituted or substituted alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, xe2x80x94C(O)Rn, xe2x80x94CO2Rn, xe2x80x94CN, xe2x80x94C(O)NRnRo, xe2x80x94C(O)NRnORo, xe2x80x94C(S)Rn, xe2x80x94C(S)ORn, xe2x80x94C(S)NRnRo, xe2x80x94NO2, xe2x80x94SORo, xe2x80x94SO2Rn, xe2x80x94SO2NRnRo, xe2x80x94SO2(NRn)(ORo), xe2x80x94SONRn, xe2x80x94SO3Rn, xe2x80x94PO(ORn)2, xe2x80x94PO(ORn)(ORo), xe2x80x94PO(NRnRo)(ORp), xe2x80x94PO(NRnRo)(NRpRq), xe2x80x94C(O)NRnNRoRp, or xe2x80x94C(S)NRnNRoRp, wherein Rn, Ro, Rp, and Rq are independently H, a substituted or unsubstituted alkyl group, cycloalkyl group, aryl group, heterocycloalkyl group, acyl group or thioacyl group, or wherein any two of the Rn, Ro, Rp, and Rq, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted,
or Z and Rd, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Rd are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group,
or Z and Z1, together with the atom to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.
Preferably, when Ra is substituted or unsubstituted heterocycloalkylalkyl, the alkyl moiety thereof is a substituted or unsubstituted saturated alkyl moiety.
Specifically, this invention relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the general Formula I: 
wherein:
R1 is H, a substituted or unsubstituted lower alkyl group or a suitable nitrogen protecting group;
R2 is an alkylcarbonyl group, an arylcarbonyl group, a cycloalkylcarbonyl group, a heterocycloalkylcarbonyl group, a heteroarylcarbonyl group, or an alkyloxycarbonyl group, wherein each of the alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl moieties in the above groups may be substituted or unsubstituted, or a suitable nitrogen protecting group;
R3 is H or a suitable substituent; or
R1 together with R2 form a suitable nitrogen protecting group; or
R2 together with R3 form a heterocycloalkyl ring or heteroaryl ring, which may be optionally substituted;
R4 is H or a suitable substituent;
the dotted line represents an optional bond;
R5 is H or a suitable substituent;
R6 is H or a substituted or unsubstituted alkyl group; or
R5 together with R6 form a heterocycloalkyl ring, which may be optionally substituted;
R7 and R10 are independently H, halogen or a substituted or unsubstituted lower alkyl group;
R8 is H or a substituted or unsubstituted lower alkyl group;
R11 is H, halogen, hydroxyl, a substituted or unsubstituted alkyl, alkoxy or alkylthio group;
R9 is a substituent having the formula: 
wherein:
R12 and R13 are independently H or lower alkyl;
m is 0 or 1;
p is an integer of from 0 to 5;
A1 is CH or N;
A2 is C(R14)(R15), N(R16) S, S(O), S(O)2, or O; where each R14, R15, and R16 is independently H or lower alkyl;
each A3 present is independently C(R14)(R15), N(R16), S, S(O), S(O)2, or O; where each R14, R15, and R16 is independently H or lower alkyl;
when p is 1, 2, 3, 4, or 5, A4 is N(R17), C(R14)(R15), or O; and when p is 0 (i.e., A3 is not present), A4 is N(R17)(R18), C(R14)(R15)(R16), and O(R18), where each R14, R15, and R16 is independently H or lower alkyl, each R17 is H, alkyl, aryl, or acyl, and each R18 is H, alkyl, or aryl;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present (i.e., m=1) and a hydrogen atom when A2 is absent (i.e., m=0); and
Z and Z1 are independently H, F, a unsubstituted or substituted alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, xe2x80x94C(O)R19, xe2x80x94CO2R19, xe2x80x94CN, xe2x80x94C(O)NR19R20, xe2x80x94C(O)NR19OR20, xe2x80x94C(S)R19, xe2x80x94C(S)OR19, xe2x80x94C(S)NR19R20, xe2x80x94NO2, xe2x80x94SOR20, xe2x80x94SO2R19, xe2x80x94SO2NR19R20, xe2x80x94SO2(NR19)(OR20), xe2x80x94SONR19, xe2x80x94SO3R19, xe2x80x94PO(OR19)2, xe2x80x94PO(OR19)(OR20), xe2x80x94PO(NR19R20)(OR21) xe2x80x94PO(NR19R20)(NR21R22), xe2x80x94C(O)NR19NR20R21, or xe2x80x94C(S)NR19NR20R21, wherein R19, R20, R21, and R22 are independently H, a substituted or unsubstituted alkyl group, cycloalkyl group, aryl group, heterocycloalkyl group, acyl group or thioacyl group, or wherein any two of the R19, R20, R21, and R22, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted,
or Z and R11, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and R11 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group,
or Z and Z1, together with the atom to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.
In another embodiment of the compounds of the above formulae, Z and Z1 are independently H, F, a unsubstituted or substituted alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, xe2x80x94C(O)R19, xe2x80x94CO2R19, xe2x80x94CN, xe2x80x94C(O)NR19R20, xe2x80x94C(O)NR19OR20, xe2x80x94C(S)R19, xe2x80x94C(S)NR19R20, xe2x80x94NO2, xe2x80x94SOR20, xe2x80x94SO2R19, xe2x80x94SO2NR19R20, xe2x80x94SO2(NR19)(OR20), xe2x80x94SONR19, xe2x80x94SO3R19, xe2x80x94PO(OR19)2, xe2x80x94PO(OR19)(OR20) xe2x80x94PO(NR19R20)(OR21), xe2x80x94PO(NR19R20)(NR21R22), xe2x80x94C(O)NR19NR20R21, or xe2x80x94C(S)NR19NR20R21, wherein R19, R20, R21, and R22 are independently H, a substituted or unsubstituted alkyl group, cycloalkyl group, aryl group, heterocycloalkyl group, acyl group or thioacyl group, or wherein any two of the R19, R20, R21, and R22, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted, or Z and Z1, together with the atom to which they are bonded, form a cycloalkyl or heterocycloalkyl group.
In yet another embodiment of the compounds of the above formulae, Z and Z1 are independently H, F, a unsubstituted or substituted alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, xe2x80x94C(O)R19, xe2x80x94CO2R19, xe2x80x94CN, xe2x80x94C(O)NR19R20, xe2x80x94C(O)NR19OR20, xe2x80x94C(S)R19, xe2x80x94C(S)NR19R20, xe2x80x94NO2, xe2x80x94SOR20, xe2x80x94SO2R19, xe2x80x94SO2NR19R20, xe2x80x94SO2(NR19)(OR20), xe2x80x94SONR19, xe2x80x94SO3R19, xe2x80x94PO(OR19)2, xe2x80x94PO(OR19)(OR20), xe2x80x94PO(NR19R20)(OR21), xe2x80x94PO(NR19R20)(NR21R22), xe2x80x94C(O)NR19NR20R21, or xe2x80x94C(S)NR19NR20R21, wherein R19, R20, R21, and R22 are independently H, a substituted or unsubstituted alkyl group, cycloalkyl group, aryl group, heterocycloalkyl group, acyl group or thioacyl group, or wherein any two of the R19, R20, R21, and R22, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted.
In addition to compounds of the above formulae, antipicornaviral agents of the invention include prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates of such compounds.
In one embodiment, the compounds of this invention useful for inhibiting the activity of picornaviral 3C proteases have the Formula I-A: 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, Z, and Z1, and the variables contained therein, are as defined above, or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.
Preferably, in the compounds of Formula I-A:
R1, R7, R8, R10, and R11 are independently H or a substituted or unsubstituted lower alkyl group;
R2 is an alkylcarbonyl group, an arylcarbonyl group, a cycloalkylcarbonyl group, a heterocycloalkylcarbonyl group, a heteroarylcarbonyl group, an aryloxycarbonyl group or an alkyloxycarbonyl group, wherein each of the alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl moieties of the above groups may be substituted or unsubstituted;
R3 is H or a suitable substituent; or
R2 together with R3 form a heterocycloalkyl ring or heteroaryl ring, which may be optionally substituted;
R4 is H or a suitable substituent;
R5 is H or a suitable substituent;
R6 is H or an unsubstituted alkyl group or a lower alkyl group optionally substituted with a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkoxyl group, an aryloxy group, an alkylthio group, an arylthio group, wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl moiety thereof may be optionally substituted; or
R5 together with R6 form a substituted or unsubstituted five- or six-membered heterocycloalkyl ring;
wherein when R3, R4, and R5 are suitable substituents, said suitable substituents may be independently selected from alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, cyano, halogen, haloalkyl (trifluoromethyl), hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, heterocycloalkyloxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, arylthio, and heteroarylthio, wherein any of the alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted with one or more suitable substituents, preferably selected from nitro, amino, cyano, halogen, haloalkyl, hydroxyl, keto, and unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, or aryloxy;
R9 is an aminocarbonylalkyl group, an alkylcarbonylaminoalkyl group, an alkylaminocarbonylalkyl group or a substituent having the formula: 
wherein:
R12 and R13 are independently H or lower alkyl;
m is 1;
p is 1 or 2;
A1 is CH or N;
A2 is C(R14)(R15), N(R16), S, (O), S(O)2, or O;
each A3 present is independently C(R14)(R15), N(R16), S, S(O), S(O)2, or O;
A4 is N(R17), C(R14)(R15), or O;
wherein each R14, R15, and R16 is independently H or lower alkyl, and each R17 is H, alkyl, aryl, or acyl;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond; and
Z and Z1 are independently H, F, a unsubstituted or substituted alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group, xe2x80x94C(O)R19, xe2x80x94CO2R19, xe2x80x94CN, xe2x80x94C(O)NR19R20, xe2x80x94C(O)NR19OR20, xe2x80x94C(S)R19, xe2x80x94C(S)NR19R20, xe2x80x94NO2, xe2x80x94SOR20, xe2x80x94SO2R19, xe2x80x94SO2NR19R20, xe2x80x94SO2(NR19)(OR20), xe2x80x94SONR19, xe2x80x94SO3R19, xe2x80x94PO(OR19)2, xe2x80x94PO(OR19)(OR20), xe2x80x94PO(NR19R20)(OR21), xe2x80x94PO(NR19R20)(NR21R22), xe2x80x94C(O)NR19NR20R21, or xe2x80x94C(S)NR19NR20R21, wherein R19, R20, R21, and R22 are independently H, a substituted or unsubstituted alkyl group, cycloalkyl group, aryl group, heterocycloalkyl group, acyl group or thioacyl group, or wherein any two of the R19, R20, R21, and R22, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted,
or Z and Z1, together with the atom to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group.
Preferably, R3, R4 and R5 may be independently selected from H, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, amino, cyano, halogen, haloalkyl (trifluoromethyl), hydroxyl, keto, alkoxy, aryloxy, cycloalkoxy, heterocycloalkoxy, alkyloxycarbonyl, aryloxycarbonyl, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroaryloxycarbonyl, heteroaryl carbonyloxy, heterocycloalkyloxycarbonyl, carboxyl, alkylamino, arylamino, dialkylamino, alkylaminocarbonyl, alkylsulfonyl, or arylsulfonyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties of any of the above substituents may be optionally substituted by one or more of haloalkyl, nitro, amino, cyano, halogen, hydroxyl, haloalkoxy, mercapto, keto or unsubstituted alkyl (except for alkyl), cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, alkylamino, dialkylamino, alkylthio or arylthio groups.
In accordance with a convention used in the art, 
is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
As used herein, the term xe2x80x9calkylxe2x80x9d represents a straight- or branched-chain saturated or unsaturated hydrocarbon, containing 1 to 10 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below. Exemplary alkyl substituents include, but are not limited to methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, propenyl, butenyl, pentenyl, ethynyl, butynyl, propynyl (propargyl, isopropynyl), pentynyl, hexynyl, and the like. The term xe2x80x9clower alkylxe2x80x9d refers to an alkyl group containing from 1 to 4 carbon atoms.
xe2x80x9cCycloalkylxe2x80x9d represents a group comprising a non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon containing from 3 to 14 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below and may be saturated or unsaturated. Exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, that may be fully saturated or partially unsaturated. Illustrative examples of cycloalkyl groups include the following: 
xe2x80x9cHeterocycloalkylxe2x80x9d represents a group comprising a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or partially unsaturated, containing 3 to 18 ring atoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents described below. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like. Illustrative examples of heterocycloalkyl groups include the following moieties: 
xe2x80x9cArylxe2x80x9d represents a group comprising an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing from 6 to 18 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents described below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include the following moieties: 
xe2x80x9cHeteroarylxe2x80x9d represents a group comprising an aromatic monovalent monocyclic, bicyclic, or tricyclic radical, containing 5 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents described below. Illustrative examples of heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl. Further examples of heteroaryl groups include the following moieties: 
Exemplary xe2x80x9csuitable substituentsxe2x80x9d that may be present on any of the above alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl groups are described herein and include alkyl (except for alkyl), aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, cyano, halogen, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, arylthio, heteroarylthio, wherein any of the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted. Preferred xe2x80x9csuitable substituentsxe2x80x9d include alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, halogen, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heteroaryloxy, and carboxyl. The alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties of any of the above substituents may be optionally substituted by one or more of alkyl (except for alkyl), haloalkyl, aryl, nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups.
If the substituents themselves are not compatible with the synthetic methods of this invention, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods. The protecting group may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley and Sons, NY (1999), which is incorporated herein by reference in its entirety. In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful in an intermediate compound in the methods of this invention or is a desired substituent in a target compound.
In the compounds of this invention, R1 and R2, independently or taken together, may be a suitable nitrogen protecting group. As indicated above, nitrogen protecting groups are well known in the art and any nitrogen protecting group that is useful in the methods of preparing the compounds of this invention or may be useful in the antipicornaviral compounds of this invention may be used. Exemplary nitrogen protecting groups include alkyl, substituted alkyl, carbamate, urea, amide, imide, enamine, sulfenyl, sulfonyl, nitro, nitroso, oxide, phosphinyl, phosphoryl, silyl, organometallic, borinic acid and boronic acid groups. Examples of each of these groups, methods for protecting nitrogen moieties using these groups and methods for removing these groups from nitrogen moieties are disclosed in T. Greene and P. Wuts, supra. Preferably, when R1 and/or R2 are independently suitable nitrogen protecting groups, suitable R1 and R2 substituents include, but are not limited to, carbamate protecting groups such as alkyloxycarbonyl (e.g., Boc: t-butyloxycarbonyl) and aryloxycarbonyl (e.g., Cbz: benzyloxycarbonyl, or FMOC: fluorene-9-methyloxycarbonyl), alkyloxycarbonyls (e.g., methyloxycarbonyl), alkyl or arylcarbonyl, substituted alkyl, especially arylalkyl (e.g., trityl (triphenylmethyl), benzyl and substituted benzyl), and the like. When R1 and R2 taken together are a suitable nitrogen protecting group, suitable R1/R2 substituents include phthalimido and a stabase (1,2-bis (dialkylsilyl))ethylene).
The terms xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d represent chloro, fluoro, bromo or iodo substituents. xe2x80x9cHeterocyclexe2x80x9d is intended to mean a heteroaryl or heterocycloalkyl group. xe2x80x9cAcylxe2x80x9d is intended to mean a xe2x80x94C(O)xe2x80x94R radical, where R is a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. xe2x80x9cAcyloxyxe2x80x9d is intended to mean an xe2x80x94OC(O)xe2x80x94R radical, where R is a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. xe2x80x9cThioacylxe2x80x9d is intended to mean a xe2x80x94C(S)xe2x80x94R radical, where R is a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. xe2x80x9cSulfonylxe2x80x9d is intended to mean an xe2x80x94SO2xe2x80x94 biradical. xe2x80x9cSulfenylxe2x80x9d is intended to mean an xe2x80x94SOxe2x80x94 biradical. xe2x80x9cSulfoxe2x80x9d is intended to mean an xe2x80x94SO2H radical. xe2x80x9cHydroxyxe2x80x9d is intended to mean the radical xe2x80x94OH. xe2x80x9cAminexe2x80x9d or xe2x80x9caminoxe2x80x9d is intended to mean the radical xe2x80x94NH2. xe2x80x9cAlkylaminoxe2x80x9d is intended to mean the radical xe2x80x94NHRa, where Ra is an alkyl group. xe2x80x9cDialkylaminoxe2x80x9d is intended to mean the radical xe2x80x94NRaRb, where Ra and Rb are each independently an alkyl group, and is intended to include heterocycloalkyl groups, wherein Ra and Rb, taken together, form a heterocyclic ring that includes the amine nitrogen. xe2x80x9cAlkoxyxe2x80x9d is intended to mean the radical xe2x80x94ORa, where Ra is an alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like. xe2x80x9cLower alkoxyxe2x80x9d groups have alkyl moieties having from 1 to 4 carbons. xe2x80x9cAlkoxycarbonylxe2x80x9d is intended to mean the radical xe2x80x94C(O)ORa, where Ra is an alkyl group. xe2x80x9cAlkylsulfonylxe2x80x9d is intended to mean the radical xe2x80x94SO2Ra, where Ra is an alkyl group. xe2x80x9cAlkylenedioxyxe2x80x9d is intended to mean the divalent radical xe2x80x94ORaOxe2x80x94 which is bonded to adjacent atoms (e.g., adjacent atoms on a phenyl or naphthyl ring), wherein Ra is a lower alkyl group. xe2x80x9cAlkylaminocarbonylxe2x80x9d is intended to mean the radical xe2x80x94C(O)NHRa, where Ra is an alkyl group. xe2x80x9cDialkylaminocarbonylxe2x80x9d is intended to mean the radical xe2x80x94C(O)NRaRb, where Ra and Rb are each independently an alkyl group. xe2x80x9cMercaptoxe2x80x9d is intended to mean the radical xe2x80x94SH. xe2x80x9cAlkylthioxe2x80x9d is intended to mean the radical xe2x80x94SRa, where Ra is an alkyl group. xe2x80x9cCarboxyxe2x80x9d is intended to mean the radical xe2x80x94C(O)OH. xe2x80x9cKetoxe2x80x9d or xe2x80x9coxoxe2x80x9d is intended to mean the diradicalxe2x95x90O. xe2x80x9cThioketoxe2x80x9d is intended to mean the diradicalxe2x95x90S. xe2x80x9cCarbamoylxe2x80x9d is intended to mean the radical xe2x80x94C(O)NH2. xe2x80x9cCycloalkylalkylxe2x80x9d is intended to mean the radical -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined as above, and is represented by the bonding arrangement present in the groups xe2x80x94CH2-cyclohexane or xe2x80x94CH2-cyclohexene. xe2x80x9cArylalkylxe2x80x9d is intended to mean the radical -alkylaryl, wherein alkyl and aryl are defined as above, and is represented by the bonding arrangement present in a benzyl group. xe2x80x9cAminocarbonylalkylxe2x80x9d is intended to mean the radical -alkylC(O) NH2 and is represented by the bonding arrangement present in the group xe2x80x94CH2CH2C(O)NH2. xe2x80x9cAlkylaminocarbonylalkylxe2x80x9d is intended to mean the radical -alkylC(O)NHRa, where Ra is an alkyl group and is represented by the bonding arrangement present in the group xe2x80x94CH2CH2C(O)NHCH3. xe2x80x9cAlkylcarbonylaminoalkyl is intended to mean the radical -alkylNHC(O)-alkyl and is represented by the bonding arrangement present in the group xe2x80x94CH2NHC(O)CH3. xe2x80x9cDialkylaminocarbonylalkylxe2x80x9d is intended to mean the radical -alkylC(O)NRaRb, where Ra and Rb are each independently an alkyl group. xe2x80x9cAryloxyxe2x80x9d is intended to mean the radical xe2x80x94ORc, where Rc is an aryl group. xe2x80x9cHeteroaryloxyxe2x80x9d is intended to mean the radical xe2x80x94ORd, where Rd is a heteroaryl group. xe2x80x9cArylthioxe2x80x9d is intended to mean the radical xe2x80x94SRc, where Rc is an aryl group. xe2x80x9cHeteroarylthioxe2x80x9d is intended to mean the radical xe2x80x94SRd, where Rd is a heteroaryl group.
If an inventive compound is a base, a desired salt may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If an inventive compound is an acid, a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
All compounds of this invention contain at least one chiral center and may exist as single stereoisomers (e.g., single enantiomers or single diastereomers), any mixture of stereosisomers (e.g., any mixture of enantiomers or diastereomers) or racemic mixtures thereof. All such single stereoisomers, mixtures and racemates are intended to be encompassed within the broad scope of the present invention. Compounds identified herein as single stereoisomers are meant to describe compounds that are present in a form that contains at least 90% of a single stereoisomer of each chiral center present in the compounds. Where the stereochemistry of the chiral carbons present in the chemical structures illustrated herein is not specified, the chemical structure is intended to encompass compounds containing either stereoisomer of each chiral center present in the compound. Preferably, however, the inventive compounds are used in optically pure, that is, stereoisomerically pure, form or substantially optically pure (substantially stereoisomerically pure) form. As used herein, the term xe2x80x9cstereoisomericxe2x80x9d purity (or xe2x80x9copticalxe2x80x9d purity) refers to the xe2x80x9cenantiomericxe2x80x9d purity and/or xe2x80x9cdiastereomericxe2x80x9d purity of a compound. Compounds that are substantially enatiomerically pure contain at least 90% of a single isomer and preferably contain at least 95% of a single isomer of each chiral center present in the enantiomer. Compounds that are substantially diastereomerically pure contain at least 90% of a single isomer of each chiral center present in the diastereomer, and preferably contain at least 95% of a single isomer of each chiral center. More preferably, the substantially enantiomerically and diasteriomerically pure compounds in this invention contain at least 97.5% of a single isomer and most preferably contain at least 99% of a single isomer of each chiral center in the compound. The term xe2x80x9cracemicxe2x80x9d or xe2x80x9cracemic mixturexe2x80x9d refers to a mixture of equal amounts of enantiomeric compounds, which encompasses mixtures of enantiomers and mixtures of enantiomeric diastereomers. The compounds of this invention may be obtained in stereoisomerically pure (i.e., enantiomerically and/or diastereomerically pure) or substantially stereoisomerically pure (i.e., substantially enantiomerically and/or diastereomerically pure) form. Such compounds may be obtained synthetically, according to the procedures described herein using optically pure or substantially optically pure materials. Alternatively, these compounds may be obtained by resolution/separation of a mixture of stereoisomers, including racemic mixtures, using conventional procedures. Exemplary methods that may be useful for the resolution/separation of stereoisomeric mixtures include chromatography and crystallization/re-crystallization. Other useful methods may be found in xe2x80x9cEnantiomers, Racemates, and Resolutions,xe2x80x9d J. Jacques et al., 1981, John Wiley and Sons, New York, N.Y., the disclosure of which is incorporated herein by reference. Preferred stereoisomers of the compounds of this invention are described herein.
Another embodiment of this invention comprises the compounds depicted by Formula I-a (as represented by Formula I, wherein the dotted line represents a bond): 
wherein:
R2 is an alkylcarbonyl group, an arylcarbonyl group, a cycloalkylcarbonyl group, a heterocycloalkylcarbonyl group, a heteroarylcarbonyl group, an aryloxycarbonyl group or an alkyloxycarbonyl group, wherein each of the alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl moieties of the above groups may be substituted or unsubstituted;
R3, R4, R5 are independently H or a suitable substituent described above, and
R1, R6, R7, R8, R9, R10, Z and Z1, and the variables contained therein, are as defined above.
Yet another embodiment of this invention comprises the compounds depicted by Formula I-b: 
wherein:
R2 is an alkylcarbonyl group, an arylcarbonyl group, a cycloalkylcarbonyl group, a heterocycloalkylcarbonyl group, a heteroarylcarbonyl group, an aryloxycarbonyl group or an alkyloxycarbonyl group, wherein each of the alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl moieties of the above groups may be substituted or unsubstituted;
Rx represents H or one or more suitable substituents;
R3 and R4 are independently H or a suitable substituent described above; and
R1, R9, R10, Z, and Z1, and the variables contained therein, are as defined above.
A further embodiment of this invention comprises the compounds depicted by Formula I-c: 
wherein:
R7, R8, and R10 are independently H or a substituted or unsubstituted lower alkyl group;
RY represents H or one or more suitable substituents;
R4 and R5 are independently H or a suitable substituent described above; and
R1, R6, R9, Z, and Z1, and the variables contained therein, are as defined above.
Another embodiment of this invention comprises the compounds depicted by Formula I-d: 
wherein:
R7, R8, and R10 are independently H or a substituted or unsubstituted lower alkyl group;
RY represents H or one or more suitable substituents;
R4 and R5 are independently H or a suitable substituent described above; and
R1, R6, R9, Z, and Z1, and the variables contained therein, are as defined above.
Yet another embodiment of this invention comprises the compounds depicted by Formula I-e (as represented by Formula I, wherein the dotted line does not represent a bond): 
wherein:
R7, R8, and R10 are independently H or a substituted or unsubstituted lower alkyl group;
RY represents H or one or more suitable substituents;
R4 and R5 are independently H or a suitable substituent described above; and
R1, R6, R9, Z, and Z1, and the variables contained therein, are as defined above.
In preferred embodiments of Formulas I-a and I-b, R2 is selected from a substituted or unsubstituted alkyloxycarbonyl group, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocycloalkylcarbonyl or heteroarylcarbonyl group. Preferably, when R2 is a substituted alkyloxycarbonyl group, R2 is an unsubstituted or substituted arylalkyloxycarbonyl group. Exemplary R2 groups include, but are not limited to benzyloxycarbonyl, methylcarbonyl, t-butylcarbonyl, trifluoromethylcarbonyl, cyclopentylcarbonyl, tetrahydrofuran-2-carbonyl, 1,3-dithiolane-2-carbonyl and the like. Preferably, R2 is a substituted or unsubstituted benzyloxycarbonyl, arylcarbonyl, or heteroarylcarbonyl group. Even more preferably, R2 is an unsubstituted or substituted benzyloxycarbonyl or heteroarylcarbonyl group, wherein the heteroaryl moiety is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S, more preferably a five-membered heterocycle having at least one nitrogen heteroatom and at least one oxygen heteroatom (e.g., unsubstituted or substituted 1,2-oxazolyl (i.e., isoxazolyl), 1,3-oxazolyl (i.e., oxazolyl), or oxadiazolyl (1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,2,5-oxadiazolyl). When the heteroaryl moiety is oxadiazolyl, unsubstituted and monomethyl-substituted 1,2,4-oxadiazolyl are preferred. In especially preferred embodiments, the heteroaryl moiety is 3-isoxazolyl or 5-isoxazolyl, either unsubstituted or substituted with one or two methyl groups and/or halogens (F, Cl, Br or I), with chlorine and fluorine being preferred. Accordingly, the heteroarylcarbonylgroup in the especially preferred embodiments is an unsubstituted or substituted 3-carbonyl-1,2-oxazolyl group (i.e., 3-carbonyl-isoxazolyl) or a 5-carbonyl-1,2-oxazolyl group (i.e., 5-carbonyl-isoxazolyl).
In preferred embodiments of the compounds of this invention, the substituent variables R3, R4, and R5, as present in the compounds of Formulas I-a, I-b, I-c, I-d, and I-e, are selected from H, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, keto, alkoxy, aryloxy, wherein any of the alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted with one or more substituents selected from nitro, amino, cyano, halogen, haloalkyl, hydroxyl, keto, and unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, or aryloxy.
In preferred embodiments of the compounds of this invention, the substituent variables Rx in the compounds of Formula I-b are selected from H, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, heterocycloalkyloxycarbonyl, carboxyl, carbamoyl, formyl, keto, thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, arylthio, and heteroarylthio, wherein any of the alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted with one or more substituents selected from nitro, amino, cyano, halogen, haloalkyl, hydroxyl, keto, and unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, or aryloxy.
In preferred embodiments of the compounds of this invention, the substituent variable Ry in the compounds of formula Formulas I-c, I-d, and I-e, are selected from H, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, heterocycloalkyloxycarbonyl, carboxyl, carbamoyl, formyl, keto, thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, arylthio, and heteroarylthio, wherein any of the alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted with one or more substituents selected from nitro, amino, cyano, halogen, haloalkyl, hydroxyl, keto, and unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, or aryloxy.
In especially preferred embodiments of Formulas I-a, I-c, I-d, and I-e, R6 is H or an unsubstituted alkyl group or an optionally substituted lower alkyl group, wherein these groups are comprised of a straight- or branched-chain saturated hydrocarbon group, a straight- or branched-chain substituted saturated hydrocarbon group, or group comprised of a straight- or branched-chain saturated hydrocarbon moiety and an unsaturated hydrocarbon moiety. When R6 is a substituted alkyl group, the point of attachment of R6 is via a saturated hydrocarbon moiety. When R6 is a substituted saturated hydrocarbon group, the saturated hydrocarbon group may be optionally substituted with a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl moiety thereof may be optionally substituted. When R6 is comprised of a saturated hydrocarbon moiety and an unsaturated hydrocarbon moiety, the saturated hydrocarbon moiety may be bound to an unsaturated hydrocarbon moiety containing one or more double-bonds or triple-bonds, the terminal positions of which may be substituted by the substituents described above, or may contain additional straight- or branched-chain saturated hydrocarbon moieties. Preferably, the unsaturated hydrocarbon moiety contains one double-bond or one triple-bond, the terminal position(s) of which may optionally contain a straight- or branched-chain saturated hydrocarbon moiety. Preferably, if the unsaturated hydrocarbon moiety contains a double-bond, both terminal positions of the double bond contain a straight- or branched-chain saturated hydrocarbon moiety. In especially preferred embodiments, R6 is H or a substituted or unsubstituted lower alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl group, or a group comprised of a straight-chain saturated hydrocarbon moiety and an unsaturated hydrocarbon moiety. Preferably, R6 is H, methyl, substituted methyl, ethyl, n-propyl, n-butyl, sec-butyl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, substituted or unsubstituted -methylthienyl or substituted or unsubstituted benzyl, wherein the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino or dialkylamino or halogen and the thienyl moiety of the substituted -methylthienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino or dialkylamino or halogen. When R6 is substituted methyl, the methyl (methylene) moiety may be substituted with an alkoxy group, an aryloxy group, an alkylthio group or an arylthio group. Most preferably, R6 is H, ethyl, 2-propyn-1-yl, -methylcyclohexyl, or substituted or unsubstituted benzyl, wherein the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy and halogen.
In the preferred embodiments of the compounds, prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, or pharmaceutically acceptable solvates of this invention Rb and R9 are defined as above and m is 1 and p is 1 or 2 (i.e., both A2 and A3 are present) or when p is 0, m is 0 (i.e, both A2 and A3 are absent). More preferably, in Rb and R9, when m is 1 and p is 1 or 2, A2 and A3 are both C(Rh)(Ri) or C(R14)(R15), respectively. More preferably, when m is 1, p is 1.
In especially preferred embodiments of Formulas I-a, I-b, I-c, I-d, and I-e, R9 is selected from xe2x80x94CH2CH2C(O)NH2; xe2x80x94CH2CH2C(O)NH-alkyl; xe2x80x94CH2NHC(O)CH3; and 
where n is 1 or 2. More preferably, R9 is 
In the preferred embodiments of the compounds prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, or pharmaceutically acceptable solvates of this invention, Z and Z1 are independently H, substituted or unsubstituted alkyl, xe2x80x94CO2Rn or xe2x80x94CO2R19, as appropriate, wherein Rn and R19 are as defined above, or Z and Z1, taken together with the atom to which they are attached, form a heterocycloalkyl group, as defined above. In another useful embodiment of the compounds of this invention, Z and/or Z1 may be xe2x80x94C(S)ORn or xe2x80x94C(S)OR19, wherein Rn and R19 are as defined above. Such compounds may be prepared using procedures described in K. Hartke, et al., Leibigs Ann. Chem., 321-330 (1989) and K. Hartke, et al., Synthesis, 960-961 (1985). Preferably, in the compounds of Formulas I-a, I-b, I-c, I-d, and I-e, Z, and Z1 are independently H, substituted or unsubstituted alkyl, xe2x80x94CO2R19, or taken together with the atom to which they are attached, form a heterocycloalkyl group, which may be optionally substituted. More preferably, Z and Z1 are independently selected from H, xe2x80x94CO2H, substituted or unsubstituted lower alkyl, xe2x80x94CO2-alkyl, xe2x80x94CO2-cycloalkyl, xe2x80x94CO2-alkylaryl (e.g., xe2x80x94CO2-benzyl), xe2x80x94CO2-alkylheteroaryl (e.g., xe2x80x94CO2-(CH2)npyridyl) or taken together with the atom to which they are attached form a heterocycloalkyl group, which may be optionally substituted. The heterocycloalkyl group may optionally contain O, N, S, and/or P and may be substituted by one or more of oxo (keto) or thioketo. In preferred embodiments of this invention, Z and Z1 are not both H. Most preferably, Z1 is H or lower alkyl and Z is xe2x80x94CO2H, substituted or unsubstitutedxe2x80x94CO2-alkyl, xe2x80x94CO2-alkylaryl, xe2x80x94CO2-alkylheteroaryl, xe2x80x94CO2-cycloalkyl, or or taken together with the atom to which they are attached form a heterocycloalkyl group, which may be optionally substituted. Exemplary Z groups include, but are not limited to substituted and unsubstituted xe2x80x94CO2-alkyl groups, which include straight- and branched-chain alkyl groups such as ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, (2,2-dimethylpropyl)-oxycarbonyl, and the like, and which include straight and branched-chain arylalkyl and heteroarylalkyl groups, such as benzyloxycarbonyl, pyridylmethyleneoxycarbonyl, and the like, substituted and unsubstituted xe2x80x94CO2-cycloalkyl groups such as cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl, and the like, or taken together with Z1 and the atom to which they are 
attached form
A preferred embodiment of this invention comprises stereoisomers of the subject compounds having the formula: 
Another preferred embodiment of this invention comprises stereoisomers of the subject compounds having the formula: 
Especially preferred embodiments of this invention comprise stereoisomers of the subject compounds having the formula: 
Specific especially preferred embodiments of this invention comprise compounds of Formulas I-axe2x80x2, I-bxe2x80x2, I-cxe2x80x2, I-dxe2x80x2, and I-exe2x80x2 as follows: 
wherein R1, R2, R3, R4, R5, R6, R9, Z, and Z1 are as previously defined; 
wherein R1, R2, R3, R4, R9, Rx, Z, and Z1 are as previously defined; 
wherein R4, R5, R6, R9, Ry, Z, and Z1 are as previously defined; 
wherein R4, R5, R6, R9, Ry, Z, and Z1 are as previously defined; and 
wherein R4, R5, R6, R9, Ry, Z, and Z1 are as previously defined.
In especially preferred embodiments of Formulas I-axe2x80x2 and I-bxe2x80x2, R2 is unsubstituted or substituted benzyloxycarbonyl, arylcarbonyl, or heteroarylcarbonyl, more preferably heteroarylcarbonyl, where the heteroaryl moiety is a five-membered heterocycle having from one to three heteroatoms selected from O, N, and S. More preferably R2 is heteroarylcarbonyl wherein the heteroaryl moiety is a five-membered heterocycle having at least one nitrogen heteroatom and at least one oxygen heteroatom (e.g., unsubstituted or substituted 1,2-oxazolyl (i.e., isoxazolyl), 1,3-oxazolyl (i.e., oxazolyl), or oxadiazolyl (1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,2,5-oxadiazolyl); preferred oxadiazolyls are unsubstituted and monomethyl-substituted 1,2,4-oxadiazolyl. In especially preferred embodiments, the heteroaryl moiety is 3-isoxazolyl or 5-isoxazolyl, either unsubstituted or substituted with one or two substituents selected from methyl and halogen, with chloro and fluoro being preferred halogen substituents.
In the especially preferred embodiments of Formulas I-axe2x80x2, I-bxe2x80x2, I-cxe2x80x2, I-dxe2x80x2, and I-exe2x80x2, R6 is selected from H or: 
wherein Rxe2x80x2 may be H or alkyl and Rxe2x80x3 may be H or independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino or dialkylamino, and halogen. 
A particularly preferred embodiment of this invention comprises a compound having the formula: 
and prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates thereof. Other useful embodiments of this invention comprise any stereoisomer or mixture of stereoisomers of the above-noted compound.
One preferred stereoisomer of this compound may be represented by the formula: 
Another preferred stereoisomer of this compound may be represented by the formula: 
An especially preferred stereoisomer of this compound may be represented by the formula: 
Preferred specific compounds include those of the Examples below, especially: 
The invention is also directed to the intermediates of Formula II, which are useful in the synthesis of certain compounds of Formula I: 
wherein the variables R1, R2, R3, R4, and Rx are as defined above, and B is H, xe2x80x94OR24 When R1 and/or R2 are independently suitable nitrogen protecting groups, any suitable nitrogen-protecting group known in the art may be used (see, e.g., Greene and Wuts, supra). Suitable R1 and R2 substituents include, but are not limited to, carbamate protecting groups such as alkyloxycarbonyl (e.g., Boc) and aryloxycarbonyl (e.g., Cbz or FMOC), alkyloxycarbonyls (e.g., methyloxycarbonyl), alkyl or arylcarbonyl, substituted alkyl, especially arylalkyl (e.g., trityl (triphenylmethyl), benzyl and substituted benzyl) and the like. Preferably, when R1 and R2 are independently suitable nitrogen protecting groups, suitable R1 and R2 substituents include, but are not limited to, Boc, Cbz, FMOC, methyloxycarbonyl and trityl. When R1 and R2 taken together are a suitable nitrogen protecting group, suitable R1/R2 substituents include phthalimido and a stabase (1,2-bis (dialkylsilyl))ethylene). R24 may be H or a suitable protecting group for a carboxyl moiety. Suitable carboxyl protecting groups are also well known in the art, examples of which may be found in Greene and Wuts, supra, and include, but are not limited to, protecting groups where R24 is alkyl, substituted or unsubstituted aryl, alkyl and/or aryl substituted silyl (e.g., t-butyldimethylsilyl (TBS)), and the like.
The invention is also directed to pharmaceutically acceptable salts of the compounds of Formula II. Preferred examples of the Formula II useful as intermediates include the following: 
and pharmaceutically acceptable salts thereof.
The antipicornaviral compounds of this invention include prodrugs, the pharmaceutically active metabolites, and the pharmaceutically acceptable salts and solvates thereof. In preferred embodiments, the compounds of Formula I, prodrugs, pharmaceutically acceptable salts, and pharmaceutically active metabolites and solvates thereof have an antipicornaviral activity, more preferably antirhinoviral activity, corresponding to an EC50 less than or equal to 100 xcexcM in the H1-HeLa cell culture assay.
A xe2x80x9cprodrugxe2x80x9d is intended to mean a compound that is converted under physiological conditions or by solvolysis or metabolically to a specified compound that is pharmaceutically active. A prodrug may be a derivative of one of the compounds of this invention that contains a moiety, such as for example xe2x80x94CO2R, or xe2x80x94PO(OR)2, that may be cleaved under physiological conditions or by solvolysis. Any suitable R substituent may be used that provides a pharmaceutically acceptable solvolysis or cleavage product. A prodrug containing such a moiety may be prepared according to conventional procedures by treatment of a compound of this invention containing, for example, an amido, carboxylic acid, or hydroxyl moiety with a suitable reagent. A xe2x80x9cpharmaceutically active metabolitexe2x80x9d is intended to mean a pharmacologically active compound produced through metabolism in the body of a specified compound. A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to mean a salt that retains the biological effectiveness of the free acids and bases of a specified compound and that is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, xcex3-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. A xe2x80x9csolvatexe2x80x9d is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine. In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that the inventive compounds, salts, and solvates may exist in different crystal forms, all of which are intended to be within the scope of the present invention and specified formulas.
The present invention is also directed to a method of inhibiting picornaviral 3C protease activity, comprising contacting the protease with an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. For example, picornaviral 3C protease activity may be inhibited in mammalian tissue by administering a compound of Formula I or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. More preferably, the present method is directed at inhibiting rhinviral protease activity. xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is alleviated by the inhibition of the activity of one or more picornaviral 3C proteases, including, but not limited to human rhinoviruses, human poliovirus, human coxsackieviruses, encephalomyocarditis viruses, meningitis virus, and hepatitis A virus. The methods of treatment for mitigation of a disease condition include the use of the compounds in this invention in any conventionally acceptable manner, for example, as a prophylactic. The activity of the inventive compounds as inhibitors of picornaviral 3C protease activity may be measured by any of the suitable methods known to those skilled in the art, including in vivo and in vitro assays. An example of a suitable assay for activity measurements is the antiviral H1-HeLa cell culture assay described herein.
Administration of the compounds of the Formula I and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates may be performed according to any of the generally accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal.
An inventive compound of Formula I or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof may be administered as a pharmaceutical composition in any pharmaceutical form recognizable to the skilled artisan as being suitable. Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols. Pharmaceutical compositions of the invention may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use or mode of administration. In preferred embodiments, the inventive pharmaceutical compositions are delivered orally, or intranasally in the form of suspensions. Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions may be routinely determined by those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration.
Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution, and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., solution), or a nonaqueous or aqueous liquid suspension. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of Formula I or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof), and preferably is made up of one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of picornaviral 3C protease activity, by any known or suitable method of administering the dose, including: topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion. A xe2x80x9ctherapeutically effective amountxe2x80x9d is intended to mean the amount of an inventive agent that, when administered to a mammal in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of the activity of one or more picornaviral 3C proteases, such as human rhinoviruses, human poliovirus, human coxsackieviruses, encephalomyocarditis viruses, menigovirus, and hepatitis A virus. The amount of a given compound of the invention that will be therapeutically effective will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, the identity of the mammal in need thereof, which amount may be routinely determined by artisans.
Preferably, the inventive compounds of Formulas I and II are prepared by the methods of the present invention, including the General Methods shown below. When stereochemistry is not specified in chemical structures, either stereocenter may be utilized. Although several intermediates are described and depicted as 2-hydroxypyridines, it is understood that such entities may also exist as the corresponding 2-pyridone tautomers. The following abbreviations also apply: Boc (tert-butoxycarbonyl), Ac (acetyl), Cbz (benzyloxycarbonyl), DMB (2,4-dimethoxybenzyl), TBS (tert-butyldimethylsilyl), TBDPS (tert-butyldiphenylsilyl), Ms (methanesulfonate), Ts (toluenesulfonate), Bn (benzyl), and Tr (triphenylmethyl). 
In General Method 1, an amino acid A (commercially available or prepared by methods described in the chemical literature) where P1 is an appropriate protecting group for the amine functionality (e.g, Cbz, Boc, or Ac), and P2 is an appropriate protecting group for the amide nitrogen (e.g, Tr), is reductively transformed into alcohol B. Compound B is subsequently converted to compound C where P3 is an appropriate protecting group for the alcohol functionality (e.g., TBS). At this point, the P1 protecting group present in C is removed and the resulting amine or salt thereof (not shown) is subjected to an amide bond forming reaction with an appropriate xcex1-hydroxycarboxylic acid (which incorporates R6 and in which R7 is H; also not shown) to provide imtermediate D. The alcohol functionality present in D is then converted to an appropriate leaving group (e.g., mesylate, tosylate) E and is coupled with 2-hydroxypyridine F (which incorporates R1, R2, R3, R4, and R5) to give intermediate G. Note that the R1 and R2 moieties present in F may be an appropriate protecting groups for the amine functionality. The P3 protecting group is subsequently removed from G and the resulting alcohol (H) is oxidized to the corresponding aldehyde (not shown) and subjected to an olefin-forming reaction to afford intermediate I (which incorporates R11, Z, and Z1). The P2 protecting group present in I is then removed to give product J. If R1 and/or R2 is/are initially a protecting group for the amine functionality, it/they may be removed from intermediates G, H, or I or product J and replaced with a different R1 and/or R2 substituent to afford alternate intermediates G, H, or I or products J. 
In General Method 2, amino alcohol K (prepared by methods described in the chemical literature), which incorporates R9 and in which R10 is H, P1 is an appropriate protecting group for amine functionality (e.g, Cbz, Boc, or Ac), and P2 is an appropriate protecting group for the amide nitrogen (e.g. DMB), is converted to compound L where P3 is an appropriate protecting group for the alcohol functionality (e.g., TBDPS). The P1 protecting group present in L is then removed and the resulting amine or salt thereof (not shown) is subjected to an amide bond forming reaction with an appropriate xcex1-hydroxycarboxylic acid (which incorporates R6 and in which R7 is H; also not shown) to provide intermediate M. The alcohol functionality present in M is then converted to an appropriate leaving group (e.g., mesylate, tosylate) N and is coupled with 2-hydroxypyridine F (which incorporates R1, R2, R3, R4, and R5) to give intermediate O. Note that the R1 and R2 moieties present in F may be an appropriate protecting group for the amine functionality. The P3 protecting group is subsequently removed from O and the resulting alcohol (P) is oxidized to the corresponding aldehyde (not shown) and subjected to an olefin-forming reaction to afford intermediate Q (which incorporates R11, Z, and Z1). The P2 protecting group present in Q is then removed to give product R. If R1 and/or R2 is/are initially a protecting group for the amine functionality, it/they may be removed from intermediates O, P, or Q or product R and replaced with a different R1 and/or R2 substituent to afford alternate intermediates O, P, or Q or products R. 
An alternate method for preparing either product J or product R is illustrated in General Method 3. An xcex1-hydroxycarboxylic acid S (either commercially available or prepared by methods described in the chemical literature) which incorporates R6 and in which R7 is H is converted to xcex1-hydroxyester T where P4 is an appropriate protecting group for the carboxylic acid functional group (e.g, methyl, benzyl, or tert-butyl). The alcohol functionality present in T is then converted to an appropriate leaving group (e.g., mesylate, tosylate, triflate) U and is coupled with 2-hydroxypyridine F (which incorporates R1, R2, R3, R4, and R5) to give intermediate V. Note that the R1 and R2 moieties present in F may be an appropriate protecting group for the amine functionality. The P4 protecting group is subsequently removed from V to afford carboxylic acid W. Independently, intermediates X and Z (prepared by methods described in the chemical literature) which incorporate R11, Z, and Z1 and in which P1 is an appropriate protecting group for the amine functionality (e.g., Cbz, Boc, or Ac) and P2 is an appropriate protecting group for the amide nitrogen (e.g., Tr), are converted to their corresponding amines Y and AA (or salts thereof), respectively. Amines AA and Y are then independently coupled with carboxylic acid W to afford intermediate I and product R, respectively. The P2 protecting group present in intermediate I is subsequently removed to afford product J. Note that, although not depicted in General Method 3, the lactam nitrogen present in intermediate X may be protected with a suitable protecting group (e.g., DMB). If such a moiety is present in X, it may be removed after coupling of W with Y to afford product R. 
A method for preparing bicyclic products k and l is illustrated in General Method 4. Thus, an appropriate pyridine g (which incorporates R1, R2, R3, and R4, and which may be optionally substituted with Rx as shown) (an example of which may prepared as described in Specific Method 7 below) in which P11 and P12 are protecting groups for the alcohol functionality (e.g., silyl ether, methyl) is subjected to an intramolecular cyclization/deprotection protocol in which both P11 and P12 are removed to give pyridone h. Note that the R1 and R2 moieties present in g may be an appropriate protecting group for the amine functionality (e.g., Cbz). The alcohol moiety present in h is then oxidized to the corresponding carboxylic acid i. This oxidation may be accomplished via an aldehyde intermediate (not shown). Carboxylic acid i is then independently coupled with amines AA and Y (or salts thereof) (prepared as described in General Method 3 above) to afford intermediate j and product l, respectively. The P2 protecting group present in intermediate j is subsequently removed to afford product k. Note that, although not depicted in General Method 4, the lactam nitrogen present in intermediate Y may be protected with a suitable protecting group (e.g., DMB). If such a moiety is present in Y, it may be removed after coupling of i with Y to afford product l. In addition, if R1 and/or R2 is/are initially a protecting group for the amine functionality, it/they may be removed from intermediates g, h, i, or j or products k or l and replaced with a different R1 and/or R2 substituent to afford alternate intermediates g, h, i, or j or products k or l. 
An alternate method for preparing a particular type of intermediate is illustrated in General Method 5. Thus, the sulfone m (which may be prepared by the method described in Org. Lett. 1999, 1, 83) in which Rx is/are H and P13 is an appropriate protecting group for the carboxylic acid functionality (e.g., methyl, ethyl, benzyl, or tert-butyl ester) is transformed into diazo compound n. This intermediate is subjected to a rhodium-catalyzed cyclization reaction involving phenylvinyl sulfone to give intermediate o (in which R3 is H). The hydroxyl group present in o is converted to the corresponding trifluoromethane sulfonate (OTf) p, and this intermediate is further transformed to the amine r via imine q. The amine present in r is derivatized with an appropriate moiety to afford intermediate s (which contains the R2 functional group and in which R1 is H). Intermediate s is subjected to a desulfurization reaction to give intermediate t and this entity is deprotected to give carboxylic acid i (in which R1, R3, R4, and Rx are H). Alternatively, intermediate s may be deprotected to give carboxylic acid u (in which R1, R3, and Rx are H) which may be utilized in place of i in General Method 4 above. 
An additional method for preparing intermediates related to i is illustrated in General Method 6. Thus, the diazo compound n (prepared in General Method 5 above) in which Rx is/are H and in which P13 is an appropriate protecting group for the carboxylic acid functionality (e.g., methyl, ethyl, benzyl, or tert-butyl ester) is subjected to a rhodium-catalyzed cyclization reaction involving nitroethylene to give intermediate v (in which R3 is H). The hydroxyl group present in v is converted to the corresponding trifluoromethane sulfonate (OTf) w, and this intermediate is further transformed to the amine y via imine x. The amine present in y is derivatized with an appropriate moiety to afford intermediate z (which contains the R2 functional group and in which R1 is H). Intermediate z is reduced to give intermediate aa and this entity is transformed to intermediate bb in which X is a halogen. Intermediate bb is subsequently deprotected to give carboxylic acid cc. If desired, intermediate aa may also be transformed into intermediate t (General Method 5 above). Alternatively, intermediate aa is transformed to intermediate dd which is subsequently deprotected to give carboxylic acid ee. Alternatively, intermediate aa is transformed to intermediate ff in which R is alkyl, acyl, sulfonyl, or acyloxy. Intermediate ff is subsequently deprotected to give carboxylic acid gg. Carboxylic acids cc, ee, and gg may each be utilized in place of i in General Method 4 above. 
An additional method for preparing intermediates related to i is illustrated in General Method 7. Thus, the diazo compound n (prepared in General Method 5 above) in which Rx is/are H and in which P13 is an appropriate protecting group for the carboxylic acid functionality (e.g., methyl, ethyl, benzyl, or tert-butyl ester) is subjected to a rhodium-catalyzed cyclization reaction involving acrylate esters or vinyl ketones to give intermediate hh (in which R3 is H and Z2 is alkyl, aryl, alkoxy, and benzyloxy). The hydroxyl group present in hh is converted to the corresponding trifluoromethane sulfonate (OTf) ii, and this intermediate is further transformed to the amine kk via imine jj. The amine present in kk is derivatized with an appropriate moiety to afford intermediate ll (which contains the R2 functional group and in which R1 is H). Intermediate 11 is subsequently deprotected to give carboxylic acid mm which may be utilized in place of i in General Method 4 above. At any point in the above sequence, if Z2 is alkoxy or benzyloxy it may be replaced with a hydroxyl functionality. The resulting carboxylic acid may subsequently be rearranged to the corresponding amine using established methods and the amine-containing intermediates may be utilized as depicted in General Method 6. For example, intermediate ll (when Z2 is OH) may be rearranged to intermediate aa (General Method 6). 
Yet another method for preparing intermediate ll is depicted in General Method 8. Thus the sodium salt of xcex1-dehydroalanine derivative nn (which incorporates R2 and in which R1 is H) (which is either commercially available or may be prepared from serine by a variety of literature techniques) is condensed with intermediate oo (which may be prepared as described in Tetrahedron Lett. 1989, 30, 3621) in which Rx is/are H and P13 is an appropriate protecting group for the carboxylic acid functionality (e.g., methyl, ethyl, benzyl, or tert-butyl ester) and in which Z2 is alkyl, aryl, alkoxy, or benzyloxy to give intermediate pp. Intermediate pp is subsequently oxidized (by a variety of literature methods) to afford intermediate ll which may be utilized as described above in General Method 7. 
An alternate method for preparing intermediate z (from General Method 6 above) is depicted in General Method 9. Thus the nitro compound qq (prepared by analogy with the method described in: J. Chem. Soc., Perkin Trans. 1 1998, 1113) which incorporates R2 and in which R1 is H and P14 is a suitable protecting group for the carboxylic acid functionality (e.g., methyl or ethyl) is condensed with intermediate rr (prepared according to: J. Heterocyclic Chem. 1992, 29, 1285) in which Rx is/are H and P13 is a suitable protecting group for the carboxylic acid functionality (e.g., methyl, ethyl, benzyl, or tert-butyl) to give intermediate ss. Intermediate ss is subsequently oxidized (by a variety of literature methods) to afford intermediate z which may be utilized as described above in General Method 6. 
General Method 10 depicts the preparation of the bicyclic pyrrole vv, starting with aldehyde tt, prepared according to the procedure described in Smith, K. M., J. Chem. Soc., Perkin Trans. I, 1973, p. 516. This compound is subjected to reductive amination conditions with an amine to give compound uu. The carboxylic acid protecting group P16 is removed, and the resulting acid is condensed intramolecularly with the secondary amine to give bicycle vv. This bicyclic compound may be coupled to amine Y or AA according to the method described in General Method 3.
The following Specific Methods may also be utilized to prepare some of the compounds described in this invention. 
Specific Method 1 describes the preparation of specific compound J1 (compound 5). Thus, commercially available amino acid A1 was reduced to alcohol B1 which, in turn, was transformed into compound C1. The Cbz moiety present in C1 was removed by hydrogenation and the resulting amine (not shown) was coupled with D-3-phenyllactic acid (commercially available) to afford intermediate D1. This latter entity was subsequently transformed to the corresponding methanesulfonate (mesylate) (E1) and was coupled with the sodium salt of 2-hydroxypyridine F1 to provide intermediate G1. The 2-hydroxypyridine F1 was prepared from commercially available 2-hydroxy-3-nitropyridine by reduction and subsequent Boc protection of the resulting amine. The silyl protecting group present in G1 was removed and the alcohol thus obtained (H1) was oxidized to the corresponding aldehyde (not shown) and subjected to an olefin-forming reaction to give intermediate I1. The Boc moiety contained in I1 was then thermally deprotected and the resulting amine (not shown) was derivatized with commercially available 5-methylisoxazole-3-carbonyl chloride to give intermediate I2. The trityl protecting group present in I2 was subsequently removed under acidic conditions to complete the preparation of specific compound J1 (compound 5). 
Specific Method 2 describes the preparation of specific compound R1 (compound 20). Thus, alcohol K1 (prepared as described in Dragovich, et al., J. Med Chem. 1999, 42, 1213) was protected to give intermediate L1. The Boc protecting group present in L1 was removed under acidic conditions and the resulting amine salt (not shown) was coupled with (2R)-3-(4xe2x80x2-fluorophenyl)-2-hydroxypropionic acid (S1, prepared as described in Specific Method 3 below) to afford intermediate M1. This latter entity was subsequently transformed to the corresponding methanesulfonate (mesylate) (N1) and was coupled with the sodium salt of 2-hydroxypyridine F2 to provide intermediate O1. The 2-hydroxypyridine F2 was prepared from commercially available 2-hydroxy-3-nitropyridine by reduction and subsequent derivatization of the resulting amine with commercially available 5-methylisoxazole-3-carbonyl chloride. The silyl protecting group present in O1 was removed and the alcohol thus obtained (P1) was oxidized to the corresponding aldehyde (not shown) and subjected to an olefin-forming reaction to give intermediate Q1. The DMB moiety contained in Q1 was then deprotected to complete the preparation of specific compound R1 (compound 20). 
Specific Method 3 describes the preparation of specific compound R2 (compound 23). Thus, commercially available Boc-D-(4-F)Phe-OH was deprotected under acidic conditions and the resulting amine salt was subjected to a diazotization/displacement protocol to provide (2R)-3-(4xe2x80x2-fluorophenyl)-2-hydroxypropionic acid (S1). This material was subsequently transformed into the corresponding trifluoromethane sulfonate (triflate) U1 via the methyl ester T1 and was coupled with the sodium salt of 2-hydroxypyridine F3 to provide intermediate V1. The 2-hydroxypyridine F3 was prepared from commercially available 2-hydroxy-3-nitropyridine by reduction and subsequent derivatization of the resulting amine with 5-chloroisoxazole-3-carbonyl chloride (prepared as described in the Experimental Section of this work). The methyl ester present in V1 was subsequently hydrolyzed under basic conditions and the resulting carboxylic acid (W1) was coupled with amine Y1 (or salt thereof) to complete the preparation of specific compound R2 (compound 23). Amine Y1 (or salt thereof) was prepared by deprotection of intermediate X1 (prepared in a manner analogous to that described in Baldwin et al., J. Org. Chem. 1971, 36, 1441). 
Specific Method 4 describes the preparation of specific compound J2 (compound 24). Thus, (2R)-3-(4xe2x80x2-fluorophenyl)-2-hydroxypropionic acid (S1, prepared as described above in Specific Method 3) was transformed into the corresponding trifluoromethane sulfonate (triflate) U2 via the benzyl ester T2 and was coupled with the sodium salt of 2-hydroxypyridine F4 to provide intermediate V2. The 2-hydroxypyridine F4 was prepared from commercially available 2-hydroxy-3-nitropyridine by reduction and subsequent derivatization of the resulting amine with trifluoroacetic anhydride. The benzyl ester present in V2 was subsequently removed by hydrogenation and the resulting carboxylic acid (W2) was coupled with amine AA1 (or salt thereof) to give intermediate I3. The trityl protecting group present in I3 was then removed under acidic conditions to complete the preparation of specific compound J2 (compound 24). Amine AA1 (or salt thereof) was prepared by deprotection of intermediate Z1 (prepared as described in Dragovich, et al. J. Med. Chem. 1998, 41, 2806). 
Specific Method 5 describes the preparation of specific compound R3 (compound 26). Thus, commercially available tert-butyl (R)-2-hydroxybutyrate (T3) was transformed into the corresponding trifluoromethane sulfonate (triflate) U3 and was coupled with the sodium salt of 2-hydroxypyridine F2 (prepared as described in Specific Method 2 above) to provide intermediate V3. The tert-butyl ester present in V3 was subsequently hydrolyzed under acidic conditions and the resulting carboxylic acid (W3) was coupled with amine Y2 (or salt thereof) to complete the preparation of specific compound R3 (compound 26). Amine Y2 (or salt thereof) was prepared by deprotection of intermediate X2, prepared according to the method disclosed in the co-pending application, U.S. Provisional Patent Application No. 60/150,358, filed Aug. 24, 1999, the disclosure of which is incorporated herein by reference. 
Specific Method 6 describes the preparation of specific compound R4 (compound 29). Thus, trifluoromethane sulfonate (triflate) U3 (prepared as described in Specific method 5 above) was coupled with the sodium salt of 2-hydroxypyridine F3 (prepared as described in Specific Method 3 above) to provide intermediate V4. The tert-butyl ester present in V4 was subsequently hydrolyzed under acidic conditions and the resulting carboxylic acid (W4) was coupled with amine Y3 (or salt thereof) to complete the preparation of specific compound R4 (compound 29). Amine Y3 (or salt thereof) was synthesized from alcohol K1 (prepared as described in Dragovich, et al., J. Med Chem. 1999, 42, 1213) by the following method. Alcohol K1 was oxidized to the corresponding aldehyde (not shown) and subjected to an olefin-forming reaction to give intermediate X3. The DMB moiety contained in X3 was then deprotected to provide intermediate X4, and this entity was deprotected under acidic conditions to afford amine Y3 (or salt thereof). 
Specific Method 7 describes the preparation of specific compound k1 (compound 36). Thus, the dianion of commercially available 2-hydroxy-6-methylnicotinonitrile was converted to intermediate a1 by methods related to those described in the literature (DeJohn, D.; Domagala, J. M.; Kaltenbronn, J. S.; Krolls, U. J. Heterocyclic Chem. 1983, 20, 1295). The nitrile functionality present in this intermediate was then converted to the corresponding carboxylic acid c1 via the primary amide b1. Intermediate c1 was subjected to a Curtius rearrangement and the resulting isocyanate was trapped with benzyl alcohol to provide carbamate d1. The hydroxyl moiety contained in d1 was selectively methylated and the resulting methyl ether (e1) was subjected to an asymmetric dihydroxylation reaction to give diol f1. This asymmetric dihydroxylation reaction can be effected utilizing a variety of commercial and non-commercial chiral additives. The primary hydroxyl moiety contained in f1 was selectively protected as the corresponding tert-butyldimethylsilyl ether (g1). This intermediate was treated with trifluoromethanesulfonic anhydride in the presence of 2,6-lutidine at low temperature followed by exposure to tetrabutylammonium fluoride to effect (i) intramolecular cyclization and (ii) silyl ether deprotection and afford alcohol h1. Alcohol h1 was oxidized to the corresponding aldehyde (not shown), and this intermediate was further oxidized to the corresponding carboxylic acid i1. Acid i1 was coupled with amine AA1 (or salt thereof) to give intermediate j1. The trityl protecting group present in j1 was then removed under acidic conditions to complete the preparation of specific compound k1 (compound 36). Amine AA1 (or salt thereof) was prepared by deprotection of intermediate Z1 (prepared as described in Dragovich, et al. J. Med. Chem. 1998, 41, 2806). 
Specific Method 8 describes the preparation of specific compounds 11 and 12 (compounds 37 and 39, respectively). Thus, the Cbz moiety present in intermediate g1 (prepared as described in Specific Method 7 above) was removed and the resulting amine (not shown) was derivatized with commercially available 5-methylisoxazole-3-carbonyl chloride to provide intermediate g2. This intermediate was converted to specific compound 11 (compound 37) by a process analogous to that described in Specific Method 7 for the conversion of intermediate g1 to intermediate j1 utilizing amine Y2 (Specific Method 5) where appropriate. During this process, a small amount of intermediate i3 was also serendipitously generated. This intermediate was transformed to specific compound 12 (compound 39) by a process analogous to that described in Specific Method 7 for the conversion of intermediate g1 to intermediate j1 utilizing amine Y2 (Specific Method 5) where appropriate. 
Specific Method 9 describes the synthesis of a bicyclic pyrrole. Alcohol m1 was oxidized with 2-iodoxybenzoic acid to give aldehyde n1, then reductively aminated with phenylalanine methyl ester and sodium cyanoborohydride to give amine o1. The t-butyl-protecting group was selectively removed, and the resulting amino acid was cyclized with DCC-HOBT to give p1. The methyl ester was cleaved with lithium hydroxide to give acid q1. Boc-protected 4S-amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acid ethyl ester X2 was deprotected with HCl, then coupled to acid q1, using HATU, to complete the preparation of compound 43.